Cryptococcosis is a major cause of mortality in patients with AIDS, causing over 600,000 deaths per year worldwide. In recent years, cryptococcosis has also emerged as a major problem among organ transplant recipients. The treatment of cryptococcosis is unsatisfactory since the disease is associated with a high morbidity and mortality even following treatment with antifungal drugs. There is an acute need for new approaches to treatment in these populations at risk. Passive antibody therapy is a particularly promising approach. This competing application proposes a research plan to investigate a new problem in immunology, which has direct relevance to the development of antibody therapy for C. neoformans-related diseases, passive antibody therapies in general and our understanding of humoral immunity. In the past funding period, we have established that the constant region (C) domain of an immunoglobulin can affect the specificity of the antibody by a mechanism that is proposed to involve structural changes in the antigen-binding site. This finding challenges the long-held dogma in immunology that viewed immunoglobulin molecules as bifunctional molecules with two independent domains, composed of a C region and a variable (V) region. Our findings challenge this dogma, and in doing so suggest a need for revisions to our views on idiotype regulation, isotype restriction, generation of antibody responses, and generation of diversity in antibody repertories. At a practical level, these findings are critically important for the design and development of chimeric and humanized antibodies for human therapy and impact our analysis of vaccine responses. The research program proposes four aims: 1) To determine the structures and antigen contact residues for V-region identical Fab fragments derived from IgG1, IgG2a, IgG2b and IgG3;2) To identify the amino acid that mediate isotype-related differences in specificity among Abs with identical V regions;3) To establish whether constant region-mediated changes in specificity extend to IgM, IgE and IgA isotypes;and 4) Construction of a second-generation mouse-human chimeric Ab suitable for human trials. At the completion of these studies we will know how the C region affects V region conformation to influence affinity, specificity, and idiotype and we will have improved immunoglobulins to C. neoformans glucuronoxylomannan suitable for subsequent clinical studies.

Public Health Relevance

Antibodies are molecules that are critically important for defending against pathogenic microbes. This research proposal proposes to investigate how the structure of antibodies vary among different antibody types and how to then use this information to make better therapeutic reagents for treatment of a very serious fungal infection that affects individuals with compromised immune systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033774-19
Application #
8390490
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Lambros, Chris
Project Start
1993-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
19
Fiscal Year
2013
Total Cost
$386,199
Indirect Cost
$153,549
Name
Albert Einstein College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Stukes, Sabriya A; Cohen, Hillel W; Casadevall, Arturo (2014) Temporal kinetics and quantitative analysis of Cryptococcus neoformans nonlytic exocytosis. Infect Immun 82:2059-67
Brown, Lisa; Kessler, Anne; Cabezas-Sanchez, Pablo et al. (2014) Extracellular vesicles produced by the Gram-positive bacterium Bacillus subtilis are disrupted by the lipopeptide surfactin. Mol Microbiol 93:183-98
Stukes, Sabriya; Casadevall, Arturo (2014) Visualizing non-lytic exocytosis of Cryptococcus neoformans from macrophages using digital light microscopy. J Vis Exp :e52084
Albuquerque, Priscila C; Fonseca, Fernanda L; Dutra, Fabianno F et al. (2014) Cryptococcus neoformans glucuronoxylomannan fractions of different molecular masses are functionally distinct. Future Microbiol 9:147-61
Rivera, Johanna; Morgenstern, Alfred; Bruchertseifer, Frank et al. (2014) Microbicidal power of alpha radiation in sterilizing germinating Bacillus anthracis spores. Antimicrob Agents Chemother 58:1813-5
Chaskes, Stuart; Cammer, Michael; Nieves, Edward et al. (2014) Pigment production on L-tryptophan medium by Cryptococcus gattii and Cryptococcus neoformans. PLoS One 9:e91901
Silva, Branca M A; Prados-Rosales, Rafael; Espadas-Moreno, Javier et al. (2014) Characterization of Alternaria infectoria extracellular vesicles. Med Mycol 52:202-10
Jain, Neena; Cordero, Radames J B; Casadevall, Arturo et al. (2013) Allergen1 regulates polysaccharide structure in Cryptococcus neoformans. Mol Microbiol 88:713-27
Fonseca, Fernanda L; Guimaraes, Allan J; Kmetzsch, Livia et al. (2013) Binding of the wheat germ lectin to Cryptococcus neoformans chitooligomers affects multiple mechanisms required for fungal pathogenesis. Fungal Genet Biol 60:64-73
Pericolini, Eva; Alunno, Alessia; Gabrielli, Elena et al. (2013) The microbial capsular polysaccharide galactoxylomannan inhibits IL-17A production in circulating T cells from rheumatoid arthritis patients. PLoS One 8:e53336

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